Chronic kidney disease affects millions of Americans and leads to many hormonal abnormalities, including elevations the phosphate-regulating hormone, fibroblast growth factor 23 (FGF23). Elevated FGF23 levels are associated with increased mortality and accelerated loss of kidney function, by unclear mechanisms. New studies indicate that FGF23 levels are also elevated in patients with acute kidney injury. Importantly, the factors that drive FGF23 levels up in either type of kidney failure are still not well understood. The PI, a junior faculty in nephrology at the Beth Israel Deaconess Medical Center, and a research faculty at the Endocrine Unit at the Massachusetts General Hospital (MGH), proposes to elucidate the mechanisms that control FGF23 in kidney failure using mouse models. Specifically, Aim1 of the application will ask what factors affect FGF23 rise in acute renal failure (a novel preliminary finding), focusing on the contributions of elevated phosphate, new synthesis by the bone, or influence of inflammation. Aim2 will ask if FGF23 levels are different in animals with different etiologies of kidney failure, trying to unravel the unexplained observation that patients with kidney failure have widely varying plasma levels of FGF23, even if other parameters, such as their serum phosphate, or their level of kidney impairment are the same. The PI's long-term career goal is to understand the mechanisms by which kidney dysfunction affects bone health, using both animal and human studies. Her immediate goals are to gain training in bone biology through animal and in vitro work, to develop kidney disease animal models, and to identify pathway(s) in the lab that can be verified and validated in human studies. Thus, in addition to lab work, she has developed a plan for further didactic training in bone biology through coursework and technical training in performing human bone biopsies. She has included in her mentoring team experts in FGF23 (the primary mentor), in osteocytes (a co-mentor) and in translational mineral metabolism studies (a co-mentor) to ensure a well-rounded group of advisors. The work proposed in this application will be performed at the Endocrine Unit at MGH, among a group of investigators with world-renoun expertise in bone, mineral metabolism regulation, and FGF23. PUBLIC HEALTH RELEVANCE: This project seeks to understand what controls the abnormal elevation of a hormone called FGF23 in people with kidney dysfunction by using animals. Elevation of FGF23 has been linked to increased chance of death and faster loss of kidney function in patients, although it is not clear if FGF23 itself, or another factor connected to it, s to blame. Thus, being able to control the rise in FGF23 may have significant impact on the lives of patients with kidney disease.